and the investigative tirabrutinib and orelabrutinib, offered comparable or superior efficacy and substantially improved cardiovascular and tolerability profiles compared to ibrutinib. For several B-cell lymphomas, zanubrutinib has emerged as a preferred agent based on prospective trial data, making it an important tool for clinicians in the VA. Waldenström’s Macroglobulinemia: A Preferred Monotherapy Waldenström’s macroglobulinemia is a rare, indolent B-cell lymphoplasmacytic lymphoma characterized by the infiltration of bone marrow with malignant lympho- plasmacytic cells and the overproduction of monoclonal immunoglobulin M paraprotein. Median age at diagno- sis exceeds 70 years, placing it squarely within the popu- lation of older veterans who are most commonly treated at VAMCs. The disease’s clinical manifestations arise from the direct infiltration of bone marrow, lymph nodes, and the spleen by malignant cells, which causes cytopenias, organomegaly, and constitutional symptoms, and the physical properties of the IgM paraprotein itself, which can produce hypervis- cosity syndrome, cryoglobulinemia, peripheral neuropathy, and the rare but serious Bing-Neel syndrome. Treatment is initiated based on symptom burden, paraprotein levels, and evidence of organ compromise rather than disease stage alone; asymptomatic patients may be observed indefinitely. Whole-genome sequencing identified the MYD88 L265P somatic mutation in more than 90% of patients with the disease. A second recurrent mutation, in the CXCR4 gene, is present in approximately 30% to 40% of patients and historically predicted attenuated responses to BTK inhibition. These molecular features have shaped both treatment selection and the comparative performance of BTK inhibitors in clinical trials. The pivotal data that offers support for zanubrutinib in Waldenström’s macroglobulinemia (WM) came from the phase III ASPEN trial, which randomized 201 patients with MYD88-mutated symptomatic WM to zanubruti- nib or ibrutinib. The primary endpoint was the combined rate of complete response and very good partial response assessed by independent review. Although the trial did not meet its primary endpoint at the initial analysis, zanubruti- nib demonstrated a numerically higher combined response rate of 28% vs. 19% for ibrutinib.2 At the long-term follow-up analysis at a median of 44.4 months, the very good partial response or complete response rate was 36.3% with zanubrutinib vs. 25.3% with ibrutinib, and the 42-month progression-free sur- vival rate was 78% for zanubrutinib compared with 70% for ibrutinib.3 The cardiovascular tolerability advantage was pronounced and consistent throughout follow-up. Atrial fibrillation occurred in 2% of zanubrutinib-treated patients vs. 15.3% of ibrutinib-treated patients at the primary analysis, a difference that persisted and widened at longer follow-up. Diarrhea, muscle spasms, hypertension, and adverse events leading to treatment discontinuation were all more common with ibrutinib. While neutropenia was more common with zanubrutinib, rates of grade 3 or higher infections were similar between arms. In patients with the CXCR4 mutation, zanubrutinib demonstrated a more favorable major response rate of 85.7% vs. 53.8% with ibrutinib, and progression-free survival was substantially better in the zanubrutinib arm.4 That finding is clinically significant as a drug that performs well regardless of CXCR4 status offers a practical advantage in settings where molecular profiling may be incomplete. The National Comprehensive Cancer Network responded to the ASPEN data by designating zanubrutinib as a category 1 preferred regimen for both primary therapy and previously treated Waldenström’s macroglobulinemia, making it the only agent to hold category 1 preferred status as a monotherapy across both treatment.5 Mantle Cell Lymphoma With TP53 Mutation: A Chemotherapy-Free Induction Platform Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma driven by the t(11;14) chromosomal translocation and defined by the overexpression of cyclin D1. It represents 6% to 7% of all non-Hodgkin lymphoma diagnoses in the U.S., but it carries a disproportionate burden among older men, the demographic that constitutes the core VA oncology patient population. Among the molecular features that stratify MCL outcomes, TP53 mutation stands out as particularly adverse: patients with TP53-mutated disease historically have had a median progression-free survival under one year with standard chemoimmunotherapy and poor long-term outcomes regardless of regimen intensity. A multicenter, phase 2 study evaluated the chemother- apy-free combination of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in 25 previously untreated patients with MCL carrying a TP53 mutation with stage II bulky and noncontiguous disease or at stage III or IV. Patients achieving complete remission with undetectable minimal residual disease (MRD) at cycle 24 were eligible for treat- ment discontinuation, introducing the possibility of fixed- duration therapy in a disease where continuous treatment 9 2
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